Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population
| Autor: | Malak Alghamdi, Susan Alhumaidi, Saeed Altala, Mirna Assoum, Aziza Chedrawi, Moeen Al-Sayed, Hisham Aldhalaan, Suzan A AlKhater, M. Abouelhoda, Turki Alshareef, Maha Alotaibi, Khalid S. Alqadi, Alya Alkaff, Syed Ahmed, Musad Abu Khaled, Suad Al Yamani, Bassem Albeirouti, Ali Al-Mehaidib, Walaa Alshuaibi, Nawal Makhseed, Ghada M H Abdel-Salam, Ewa Goljan, Zuhair Rahbeeni, Maisoon Almugbel, Shaza Makki, Ranad Albar, Fuad Al Mutairi, Khalid Alsaleem, Hanaa Banjar, Fahad A. Bashiri, Abdulaziz Bin Manee, Mona Alsaleh, Marwan Shaheen, Mohammed Fawzy, Sami Wali, Fahad Almohareb, Hisham Alkuraya, Shakir Bahzad, Ayman Shawli, Wesam Kurdi, Wajeeh Aldekhail, Somaya Alzelaye, Rand Arnaout, Abdullah Alsonbul, Sami Al-Hajjar, Saeed Hassan, Sameena Khan, Mohammed AlBalwi, Khalid Awartani, Sulaiman M. Al-Mayouf, Amal Alhashem, Hamoud Al-Mousa, Abdulaziz Alsemari, Hadeel Elbardisy, Mohamed El-Kalioby, Edward Cupler, Bandar Al-Saud, Hadeel Alghamdi, Isam Salih, Saadeh Sermin, Fahad Alsohaibaini, Shapar Nahrir, Hibah Alruwaili, Hamad Al-Zaidan, Nada Alsahan, Abdullah Alfaifi, Dalal K. Bubshait, Mohammed Nasr, Ahmed Alnahari, Ameen Tajuddin, Maged H. Hussein, Muddathir H Hamad, Asma Akilan, Afaf Alsagheir, Dorota Monies, Shamsad Shahrukh, Emadia Alaki, Tariq Abalkhail, Ahmed Sahly, Hamsa T. Tayeb, Badi Alenazi, Fowzan S. Alkuraya, Mohammed Al-Owain, Mohammed Abanemai, Ali Al-Ahmari, Maha Faden, Neama Meriki, Amal Alqasmi, Talal A. Basha, Hatem Murad, Hanna Akleh, Nabil Moghrabi, Asma I. Tahir, Abdulhadi Altalhi, Amal Jaafar, Ola Jarrad, Salah Baz, Abdullah Tamim, Ibraheem F. Abosoudah, Shazia Subhani, Manal Badawi, Raashida Sulaiman, Essam Al-Sabban, Brian F. Meyer, Talal Algoufi, Alya Qari, Mohammed Mahnashi, Hasan Al-Dhekri, Saeed Bohlega, Rafiullah Rafiullah, Naif A.M. Almontashiri, Mustafa A. Salih, Shahrukh K. Hashmi, Ibrahim Ghemlas, Zeeshan Shah, Abdullah Alashwal, Ehab Tous |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Candidate gene Population Saudi Arabia Germline mosaicism Genes Recessive Consanguinity 030105 genetics & heredity Biology Article Cohort Studies 03 medical and health sciences Pregnancy Genotype Exome Sequencing Genetics Humans Genetic Predisposition to Disease Allele education Child Exome Exome sequencing Genetics (clinical) education.field_of_study Homozygote Correction Genetic Diseases X-Linked 030104 developmental biology Phenotype Mutation Female |
| Zdroj: | The American Journal of Human Genetics. 105:879 |
| ISSN: | 0002-9297 |
| Popis: | We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort’s genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing. |
| Databáze: | OpenAIRE |
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